Inhibition of the Akt1-mTORC1 Axis Alters Venous Remodeling to Improve Arteriovenous Fistula Patency

Scientific Reports
Xiangjiang GuoAlan Dardik

Abstract

Arteriovenous fistulae (AVF) are the most common access created for hemodialysis, but up to 60% do not sustain dialysis within a year, suggesting a need to improve AVF maturation and patency. In a mouse AVF model, Akt1 regulates fistula wall thickness and diameter. We hypothesized that inhibition of the Akt1-mTORC1 axis alters venous remodeling to improve AVF patency. Daily intraperitoneal injections of rapamycin reduced AVF wall thickness with no change in diameter. Rapamycin decreased smooth muscle cell (SMC) and macrophage proliferation; rapamycin also reduced both M1 and M2 type macrophages. AVF in mice treated with rapamycin had reduced Akt1 and mTORC1 but not mTORC2 phosphorylation. Depletion of macrophages with clodronate-containing liposomes was also associated with reduced AVF wall thickness and both M1- and M2-type macrophages; however, AVF patency was reduced. Rapamycin was associated with improved long-term patency, enhanced early AVF remodeling and sustained reduction of SMC proliferation. These results suggest that rapamycin improves AVF patency by reducing early inflammation and wall thickening while attenuating the Akt1-mTORC1 signaling pathway in SMC and macrophages. Macrophages are associated with AVF wall thi...Continue Reading

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Citations

Oct 15, 2019·Vascular Investigation and Therapy·Jolanta GoreckaAlan Dardik
Jan 22, 2021·Arteriosclerosis, Thrombosis, and Vascular Biology·Yutaka Matsubara (松原裕)Alan Dardik
Feb 6, 2021·Journal of Vascular Surgery. Vascular Science·Ryosuke TaniguchiAlan Dardik
Jan 1, 2020·Journal of Vascular Surgery. Vascular Science·Yutaka MatsubaraAlan Dardik
Jun 3, 2021·International Journal of Molecular Sciences·Yu-Chung ShihDer-Cherng Tarng
Aug 10, 2021·Frontiers in Cardiovascular Medicine·Shin Mei ChanAlan Dardik

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Clinical Trials Mentioned

NCT02513303
NCT01595841

Software Mentioned

GraphPad
Prism
Image J
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